Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)c(C)n2)C1=O
Yield: 72.7 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (202 mg) described in Preparation Example 248 and 1-acetylimidazolidin-2-one (77 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (164 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:19][C@H:5]2[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:8][C@@:4]2([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:3]1.[CH3:36][O:37][CH:38]1[C:43](=O)[CH2:42][CH2:41][O:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:36][O:37][CH:38]1[CH:43]([NH:1][C@@H:2]2[CH2:19][C@H:5]3[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:8][C@@:4]3([C:20]([N:22]3[CH2:31][CH2:30][C:29]4[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=4[CH2:23]3)=[O:21])[CH2:3]2)[CH2:42][CH2:41][O:40][CH2:39]1
Reactant: COC1COCCC1=O
Reactant: N[C@@H]1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step A (difluoroacetate, 97.45 mg, 0.136 mmol), 3-methoxydihydro-2H-pyran-4(3H)-one (35.4 mg, 0.272 mmol), 4 Å molecular sieves (60 mg) and TEA (0.19 mL, 1.36 mmol) in DCM (4 mL) was stirred at rt for 2 h, followed by addition of sodium triacetoxyborohydride (46.12 mg, 0.218 mmol). The resulting mixture was stirred at rt overnight. The reaction was quenched by addition of saturated NaHCO3 aqueous solution, extracted with DCM, dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (eluent: 5% 7N NH3 in MeOH in DCM) to give the product as a yellow foam. 1H-NMR (400 MHz, CDCl3): δ 1.56-2.12 (m, 7H), 2.31 (br. s., 1H), 2.55-2.67 (m, 1H), 3.06-3.21 (m, 3H), 3.24-4.16 (m, 14H), 4.71 (br. s., 2H), 5.12 (s, 2H), 7.29-7.44 (m, 5H), 7.69 (br. s., 1H), 8.72 (br. s., 1H); LC/MS: C31H37F3N4O5: m/z 603.0 (M+H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
To a solution of crude ethyl 9-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 64) (74.9 g, assumed 0.103 moles) in warm absolute ethanol (330 ml) was added sodium ethoxide (1.2 g, 0.018 moles) in portions over 23 hours. The resultant mixture was stirred for a further 3 hours and then glacial acetic acid (1.5 ml) was added. The mixture was concentrated in vacuo to give the crude product as a light brown foam (63.7 g) that was used as such for the next step. The crude product can be purified by flash chromatography on silica gel eluting with a gradient system of 5% v/v isopropanol in dichloromethane changing to 7.5% v/v isopropanol in dichloromethane changing to 10% v/v isopropanol in dichloromethane followed by crystallisation from tertiary-butyl methyl ether to give the title compound as colourless crystals, m.p. 118-120° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>CN(C=O)C>[CH:7]([C:5]1[S:6][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:3][CH:4]=1)=[O:8]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)s1
Temperature: 137.5 °C
Yield: 56 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde (2.41 g, 12.6 mmol), DMF (40 mL), potassium carbonate (1.75 g, 12.6 mmol), tert-butyl acrylate (8 mL, 56.5 mmol), and CombiPhos-Pd6 (200 mg, CombiPhos Catalysts, Inc., P.O. Box 220, Princeton, N.J. 08542) was heated in a 135 to 140° C. oil bath overnight. The solvent was evaporated, the residue stirred in DCM, and the mixture filtered through a pad of diatomaceous earth. The solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with 20% EtOAc/hexane to give an orange solid (1.68 g), m/e=239 (M+1). 1H NMR (CDCl3) ppm: 1.54 (9H, s), 6.36 (1H, d), 7.28 (1H, d), 7.64 (1H, d), 7.68 (1H, d), 9.9 (1H, s).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].Cl.[CH3:21][NH:22][O:23][CH3:24].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.89 mL, 35.184 mmol) was added slowly to a mixture of commercially available 4-nitrobenzoic acid (3.0 g, 17.592 mmol), N,O-dimethylhydroxylamine hydrochloride (1.92 g, 19.351 mmol), and EDCI (4.05 g, 21.11 mmol) in CH2Cl2 (30 mL). The mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture as stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4, then filtered. The solvent was removed under reduced pressure and the residual oil chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>C1COCC1.CCOC(C)=O>[CH2:13]([N:6]([CH2:5][C@H:2]1[CH2:3][O:4][C:22]([NH2:21])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCN(C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(C[C@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 74.8 %

Procedure:
To a stirred solution of (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (128 mg) at r.t. in THF (5 ml) under an argon atmosphere were added potassium carbonate (182 mg) and a solution of cyanogen bromide (140 mg) in THF (5 ml). Stirring at r.t. was continued for 21 h. The mixture (off-white suspension) was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to provide (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (108 mg, 75%) as an off-white solid. MS (ISP): 220.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])/[C:9](/[S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[CH:24]\[C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(CSc1ccc(Br)cc1)c1ccccc1Br
Product: O=C(/C(=C\c1ccc(Br)cc1)Sc1ccc(Br)cc1)c1ccccc1Br

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(2-bromophenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) and triethylamine (2.77 mL, 20 mmol) in CH2Cl2 (20 mL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (1.15 mL, 15 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.97 g, brown oil, 70% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N

Procedure:
Compound J1was prepared from (4-chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester (A6) (22.12 g, 85 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[N:7][N:6]=1.N.[CH3:32][C:33]([CH3:35])=O>CO>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[CH2:3][NH:4][C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[C:13]3=[C:33]([CH3:35])[CH3:32])=[N:7][N:6]=1
Reactant: N[C@H](CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: N
Solvent: CO
Product: CC(C)=C1C(=O)Nc2ccc(-c3nnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc21
Reaction time: 1 h

Procedure:
Example 2 (5-(5-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)indolin-2-one) (40 mg, 46 μmol) was dissolved in 1 mL of anhydrous acetone. To the resulting solution was added 2.0 mL of 2.0M ammonia in MeOH. The resulting mixture was stirred for one hour. After removing the solvent, the title compound was obtained as a white solid (20 mg, 48%). LCMS (API-ES) m/z (%): 474.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.45 (s, 3H) 2.59 (s, 3H) 3.06-3.18 (m, 2H) 3.54-3.65 (m, 1H) 3.66-3.76 (m, 1H) 3.86-3.96 (m, 1H) 6.94 (d, J=8.22 Hz, 1H) 7.49-7.57 (m, 3H) 7.62-7.70 (m, 2H) 8.00 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][C:16]([NH2:21])=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=2)[CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][C:16]([NH2:21])=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=2)[CH:12]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCNC(=O)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cnc(Cn2cc(C#CCN)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of {3-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (see previous example, 22 mg) in DCM (3 mL) was treated with TFA (0.6 mL) at rt for 15 min. Evaporation, work-up (DCM/sat. aq. NaHCO3), drying (Na2SO4), and evaporation gave the title compound as an oil. tR=3.85 min. 1H NMR (CDCl3) δ 8.24 (s, 1H), 7.06 (s, 1H), 5.32 (s, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:11][NH:12][C:13]([C:15]1[CH:33]=[CH:32][C:18]2[O:19][CH2:20][CH:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:22][C:17]=2[C:16]=1[CH3:34])=[O:14])([CH3:10])([CH3:9])[CH3:8].[CH3:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([CH3:45])[CH:44]=1)[C:39](Cl)=[O:40].CCOCC.CCCCCC>C(OCC)(=O)C>[C:7]([N:11]([C:39](=[O:40])[C:38]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:36]([CH3:35])[CH:37]=1)[NH:12][C:13]([C:15]1[CH:33]=[CH:32][C:18]2[O:19][CH2:20][CH:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:22][C:17]=2[C:16]=1[CH3:34])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: Cc1c(C(=O)NNC(C)(C)C)ccc2c1OC(CO[Si](C)(C)C(C)(C)C)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(CO[Si](C)(C)C(C)(C)C)CO3)C(C)(C)C)c1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a round bottom flask equipped with magnetic stirring was added ethyl acetate (7 mL), 25 wt % aqueous potassium carbonate solution (2.03 g, 3.67 mmol), and 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid N′-tert-butyl hydrazide (0.50 g, 1.22 mmol). To this was added 3,5-dimethylbenzoyl chloride (0.31 g, 1.84 mmol). Stirring was continued for 18 hours. The reaction was diluted with ethyl acetate and the phases separated. The organic phase was washed once with water, once with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was flash chromatographed on silica gel eluting with 20% ether/hexane, then 50% ether/hexane to give a white solid, 3,5-dimethylbenzoic acid N-tert-butyl-N′-[3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carbonyl]-hydrazide, (0.50 g, 0.92 mmol) in 76% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 0.10 (s, 6H), 0.90 (s, 9H), 1.59 (s, 9H), 1.89 (s, 3H), 2.25 (s, 6H), 3.92 (m, 2H), 4.05 (m, 1H), 4.22 (m, 1H), 4.34 (m, 1H), 6.33 (d, 1H), 6.56 (d, 1H), 7.02 (s, 1H), 7.13 (s, 2H), 9.49 (s, 1H); TLC: Rf=0.30 (1:1 ether/hexane).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH2:27][CH2:26][CH2:25][CH2:24][C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(CCCNC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(CCCN)nc3c2C(=O)NC3)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of tert-butyl 3-(6-(2,4-dimethoxybenzyl)-5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)propylcarbamate (1.7 mg, 0.003 mmol) in TFA (2 mL) was stirred at 70° C. for 2 h. The mixture was purified by reverse phase preparative HPLC. The fractions were collected and concentrated to give a TFA salt of the title compound as a white solid (0.6 mg, 65%). 1H NMR (500 MHz, CD3OD) δ ppm 2.11-2.26 (m, 2H), 2.30-2.45 (m, 3H), 2.92-3.09 (m, 4H), 4.39 (s, 2H), 6.98 (d, J=8.34 Hz, 1H), 7.16-7.35 (m, 1H), 7.51 (s, 1H), 7.65 (d, J=8.59 Hz, 1H). [M+H] calc'd for C16H19N5O, 298. found, 298.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.O1CCCC1.[O:14]=[C:15]([CH3:23])[CH2:16][P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19].C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1>O>[N+:33](=[C:16]([P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19])[C:15](=[O:14])[CH3:23])=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.32 g, 13.2 mmol) in 100 mL 6/1 benzene/tetrahydrofuran was added dimethyl 2-oxopropylphosphonate (2.0 g, 12 mmol) dropwise at 0° C. After the addition, the mixture was stirred at 0° C. for 1 hour and p-toluenesulfonyl azide (13% in toluene, 19.2 g, 12.6 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. Water was added and extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated to provide the crude title compound which was used in the next step without purification. MS (DCI/NH3) m/z 193 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13]O.CN(C=O)C>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(I)ccc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Yield: 30 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-3-methoxybenzene. Yield 30%, white solid. 1H NMR (DMSO-d6, 400 MHz): .is 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.74 (s, 3H), 4.53 (s, 2H), 5.20 (s, 2H), 6.83 (m, 1H) 6.96 (m, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H). mp 107-108° C. MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Clc1ccnc(Cl)n1
Product: Clc1nccc(N2CCCc3ccccc32)n1

Procedure:
Using an analogous method to that described in Method 3, but starting from 2,4-dichloropyrimidine and 1,2,3,4-tetrahydroquinoline, the product was obtained. MS (MH+): 246, 248.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)=O.Cl>O1CCCC1>[Br:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=2)=[CH2:17])[CH:21]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CC(C)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(OC(C)C)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 12.0 mL, 0.9 eq) was added dropwise to a solution of 1-bromo-4-isopropoxy-benzene (4.8 g, 22 mmol, 1.0 eq) in tetrahydrofuran (20 mL) at −78° C. After stirring 30 min 3-bromoacetophenone (3.3 mL, 1.1 eq) in tetrahydrofuran (20 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with 1 N HCl (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude material was dissolved in acetic acid (50 mL) and sulfuric acid (10 mL) and the mixture was warmed to 75° C. for 30 min, cooled at room temperature and 1 N NaOH was added up to pH=7. The aqueous phase was extracted with dichloromethane (3×10 mL), dried (sodium sulfate) the solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (1.8 g, 25%);
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([F:45])[C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[N:30](COCC2C=CC=CC=2)[S:29]1(=[O:44])=[O:43])[CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][S:21]([CH3:24])(=[O:23])=[O:22])C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[F:45][C:26]1[CH:25]=[C:11]([CH:10]=[C:9]([OH:8])[C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[NH:30][S:29]1(=[O:44])=[O:43])[CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][S:21]([CH3:24])(=[O:22])=[O:23]
Reactant: Cc1ccc(OS(C)(=O)=O)c(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(OS(C)(=O)=O)c(Cc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2)c1
Reaction time: 18 h

Procedure:
To a solution of methanesulfonic acid 2-[3-benzyloxy-4-(5-benzyloxymethyl-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-5-fluorobenzyl]-4-methylphenyl ester (85 mg) in EtOH (3 mL) and EtOAc (6 mL) is added 5% Pd/C (75 mg) and the mixture is hydrogenated at 1 atm for 18 h. The catalyst is filtered and washed with EtOH (3×). Solvent is evaporated to near dryness before water and acetonitile is added to form a solution. It is then lyophilized to give the title compound: MS (M−H)−=443.